As disclosed in U.S. Pat. No. 6,384,251, organic compounds having an allylic hydrogen atom(s) have been reacted with a combination of a chromium compound and an N-hydroxy dicarboxylic acid imide under conditions sufficient to affect oxidation of the allylic hydrogen(s) on the organic compound. Similarly, U.S. Pat. No. 6,111,118 discloses that olefinic compounds can be allylically oxidized by: (i) dissolving the olefinic compound in a suitable mixture of a water miscible organic solvent, a water immiscible organic solvent and the alkyl hydroperoxide, (ii) incorporating periodic acid or metal periodate and a suitable amount of water into the reaction mixture, and then (iii) optionally pressurizing the reaction vessel with air or nitrogen.
Reaction with methyl(trifluoromethyl)dioxirane at −40° C. with vitamin D2 or its 3β-acetyl derivative has resulted in a high yield (78–80%) of the corresponding tetraepoxide as a single diastereoisomer having the 5,6(β);7,8(β);10,19(α);22,23 (pseudo-α) configuration. Curici, et al., Oxidation of Natural Targets by Dioxiranes. 4. High Stereo- and Regioselective Conversion of Vitamin D2 to Its (all-R) Tetraepoxide and C-25 Hydroxy Derivative, J. Am. Chem. Soc., 118(45), 11089–11092 (1996). Dioxiranes have also been shown to smoothly oxidize tertiary C—H bonds of saturated spiroketals. Amone, et al., G. J. Org. Chem. 1994, 59, 5511.
The cephalostatins and ritterazines comprise a family of forty-five structurally unprecedented marine products with extreme cytotoxicity against human tumors. Outer-Ring Stereochemical Modulation of Cytotoxicity in Cephalostatins, LaCour et al. Org. Lett., 2 (1), 33–36, 2000. The comparison of the biological activity in the cephalostatin and ritterazine series of marine natural products proved cephalostatin 1 to be the most active compound. The very complex and quite unusual bis-steroidal pyrazine structure of this compound, shown below as Formula (I), was first synthesized by the group of P. Fuchs in the United States. T. G. LaCour, C. Guo, S. Bhandaru, M. R. Boyd, P. L. Fuchs. J. Am. Chem. Soc. 120, 692 (1998).

At present, there are forty-five known trisdecacyclic (thirteen rings) pyrazines (cephalostatins and ritterazines) that have been isolated from two very different marine organisms. In addition to the fascinating topology and biosynthetic origin of these compounds, great interest centers on their outstanding potential as antineoplastic agents. Cephalostatin 1 appears to be the most potent inhibitor of the family with an ED50 10−7–10−9 mg/mL in the P38 cell line.
However, it has proven difficult to oxidatively prepare intermediates for synthesis of (−) analogs of the cephalostatin/ ritterazine family of marine natural products using dioxiranes. As illustrated in Scheme 1 of FIG. 1, dioxiranes DMDO and TFDO were unable to affect the desired sequential allylic oxidation of the spiroketal 1. Instead, as illustrated in FIG. 1, efforts to oxidize the spiroketal 1 using DMDO and TFDO led to undesired complex mixtures derived from the epoxy isomers of 4. Neither of the epoxy isomers of 4 undergo useful C—H oxidation using dioxiranes even after extended reaction times.
More generally, while dioxiranes have been used to oxidize natural products, the conditions employed in such oxidations may be somewhat harsh in comparison to the present invention. While in some cases the oxidation may be regioselective (one direction of bond making or breaking occurs preferentially over all other possible directions) and stereospecific, but can lead to undesirable side products. For example, as illustrated in the aforementioned spiroketal example, oxidative use of dioxiranes can lead to the formation of unwanted epoxides.
In contrast to the prior art, the present invention therefore is directed to a stereoselective, preferably a stereospecific oxidative method having wide application in the oxidation of a variety of substrates. Ideally, for application in combinatorial chemistry libraries, such method oxidizes a diverse group of substrates and is chemoselective, preferably chemospecific (i.e., there will be one preferred reaction for a substrate having one of two or more different functional groups). The method is versatile enough to oxidize substrates ranging from branched or unbranched monocyclic compounds such as cyclohexane and ethyl benzene to polycyclic compounds such as the aforementioned spiroketal containing a steroidal functionality.
Because of its chemospecificity, the method avoids unwanted side reactions such as the aforementioned spiroketal epoxidation. Finally, and of great importance in industrial application, the method is catalytic, thereby resulting in a minimal waste stream.